TRAF6 Activation in Multiple Myeloma: A Potential Therapeutic Target

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• 作者：Hong Liu¹ ; ² ; Samantha Tamashiro¹ ; Stavroula Baritaki¹ ; Manuel Penichet³ ; Youhua Yu² ; Haiming Chen⁴ ; James Berenson⁴ ; Benjamin Bonavida¹ ; ^{bbonavida@mednet.ucla.edu}
• 关键词：MM ; Osteolytic bone lesions ; RANK/RANKL ; TRAF6 ; TRAF6 decoy peptides
• 刊名：Clinical Lymphoma Myeloma and Leukemia
• 出版年：2012
• 期刊代码：pca95_21522650
• 类别：med
• 出版时间：June, 2012
• 卷：12
• 期：3
• 页码：155-163
• 文件大小：518 K

摘要

Multiple myeloma (MM) is an incurable B-lymphocyte malignancy. New therapeutic options have become available during the past several years; however nearly all patients acquire resistance to currently available therapeutic agents. Mechanisms contributing to the pathogenesis and chemoresistance of MM include genetic abnormalities, chromosomal translocations, gene mutations, the interaction between MM cells and the bone marrow microenvironment, and defects in the apoptotic signaling pathways. Survival signaling pathways associated with the pathogenesis of MM and bone marrow stromal cells play crucial roles in promoting growth, survival, adhesion, immortalization, angiogenesis, and drug resistance. The receptor activator of nuclear factor-kappa B/receptor activator of nuclear factor-kappa B ligand/tumor necrosis factor receptor-associated factor (RANK/RANKL-TRAF6) signal pathway mediates osteolytic bone lesions through the activation of the NF-魏B and Janus kinase/signal transducer and activator of transcription (JNK) pathways in osteoclast precursor cells and thus contributes to the main clinical manifestations of bone disease. TRAF6 has also been identified as a ligase for Akt ubiquitination and membrane recruitment and its phosphorylation on growth factor stimulation. The inhibition of TRAF6 by silencing RNA or by decoy peptides decreases MM tumor cell proliferation and increases apoptosis as well as bone resorption. Some proteasome inhibitors and benzoxadiazole derivatives showed inhibitory effects on the activity and function of TRAF6. Overall, we propose that TRAF6 may be considered as a potential therapeutic target for the treatment of MM.